Genetic Variant APOL1:c.-19-65dupA (chr22-36254862-C-CA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_003661.4(APOL1):c.-19-65dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00851 in 1,373,234 control chromosomes in the GnomAD database, including 157 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.022 ( 119 hom., cov: 32)

Exomes 𝑓: 0.0068 ( 38 hom. )

Consequence

APOL1
NM_003661.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.189

Publications

0 publications found

Variant links:

Genes affected

APOL1 (HGNC:618): (apolipoprotein L1) This gene encodes a secreted high density lipoprotein which binds to apolipoprotein A-I. Apolipoprotein A-I is a relatively abundant plasma protein and is the major apoprotein of HDL. It is involved in the formation of most cholesteryl esters in plasma and also promotes efflux of cholesterol from cells. This apolipoprotein L family member may play a role in lipid exchange and transport throughout the body, as well as in reverse cholesterol transport from peripheral cells to the liver. Several different transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

APOL1 Gene-Disease associations (from GenCC):

focal segmental glomerulosclerosis 4, susceptibility to
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

APOL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0738 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003661.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APOL1	NM_003661.4	MANE Select	c.-19-65dupA	intron	N/A	NP_003652.2
APOL1	NM_145343.3		c.30-65dupA	intron	N/A	NP_663318.1	O14791-2
APOL1	NM_001136540.2		c.-58-26dupA	intron	N/A	NP_001130012.1	O14791-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APOL1	ENST00000397278.8	TSL:1 MANE Select	c.-19-75_-19-74insA	intron	N/A	ENSP00000380448.4	O14791-1
APOL1	ENST00000319136.8	TSL:1	c.30-75_30-74insA	intron	N/A	ENSP00000317674.4	O14791-2
APOL1	ENST00000438034.6	TSL:4	c.30-36_30-35insA	intron	N/A	ENSP00000404525.2	B1AH94

Frequencies

GnomAD3 genomes

AF:

0.0222

AC:

3289

AN:

148476

Hom.:

117

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0759

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00951

Gnomad ASJ

AF:

0.000584

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000850

Gnomad FIN

AF:

0.000102

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000404

Gnomad OTH

AF:

0.0192

GnomAD2 exomes

AF:

0.0103

AC:

1608

AN:

155440

AF XY:

0.00815

show subpopulations

Gnomad AFR exome

AF:

0.100

Gnomad AMR exome

AF:

0.00896

Gnomad ASJ exome

AF:

0.00221

Gnomad EAS exome

AF:

0.000847

Gnomad FIN exome

AF:

0.000900

Gnomad NFE exome

AF:

0.00266

Gnomad OTH exome

AF:

0.00551

GnomAD4 exome

AF:

0.00684

AC:

8379

AN:

1224654

Hom.:

Cov.:

AF XY:

0.00618

AC XY:

3778

AN XY:

611300

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0849

AC:

2413

AN:

28434

American (AMR)

AF:

0.00804

AC:

310

AN:

38562

Ashkenazi Jewish (ASJ)

AF:

0.00530

AC:

114

AN:

21506

East Asian (EAS)

AF:

0.00519

AC:

171

AN:

32946

South Asian (SAS)

AF:

0.00198

AC:

148

AN:

74764

European-Finnish (FIN)

AF:

0.00307

AC:

141

AN:

45976

Middle Eastern (MID)

AF:

0.00807

AC:

AN:

4090

European-Non Finnish (NFE)

AF:

0.00488

AC:

4529

AN:

927760

Other (OTH)

AF:

0.0103

AC:

520

AN:

50616

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.324

Heterozygous variant carriers

873

1747

2620

3494

4367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

218

436

654

872

1090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0222

AC:

3302

AN:

148580

Hom.:

119

Cov.:

AF XY:

0.0215

AC XY:

1560

AN XY:

72468

show subpopulations

African (AFR)

AF:

0.0760

AC:

3085

AN:

40590

American (AMR)

AF:

0.00950

AC:

142

AN:

14946

Ashkenazi Jewish (ASJ)

AF:

0.000584

AC:

AN:

3422

East Asian (EAS)

AF:

0.00

AC:

AN:

5088

South Asian (SAS)

AF:

0.000638

AC:

AN:

4702

European-Finnish (FIN)

AF:

0.000102

AC:

AN:

9784

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000404

AC:

AN:

66794

Other (OTH)

AF:

0.0190

AC:

AN:

2052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

141

283

424

566

707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.0251

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.19

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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22-36254862-CAA-CAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over